STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair

被引：3

作者：

van den Heuvel, Diana ^{[1
]}

Rodriguez-Martinez, Marta ^{[2
]}

van der Meer, Paula J. ^{[1
]}

Moreno, Nicolas Nieto ^{[3
]}

Park, Jiyoung ^{[4
]}

Kim, Hyun-Suk ^{[4
]}

van Schie, Janne J. M. ^{[1
]}

Wondergem, Annelotte P. ^{[1
]}

D'Souza, Areetha

Yakoub, George ^{[1
]}

Herlihy, Anna E. ^{[2
]}

Kashyap, Krushanka ^{[2
,3
]}

Boissiere, Thierry ^{[3
]}

Walker, Jane ^{[2
]}

Mitter, Richard ^{[6
]}

Apelt, Katja ^{[1
]}

de Lint, Klaas ^{[7
]}

Kirdok, Idil ^{[7
]}

Ljungman, Mats ^{[8
,9
,10
]}

Wolthuis, Rob M. F. ^{[7
]}

Cramer, Patrick ^{[11
]}

Scharer, Orlando D. ^{[4
,5
]}

Kokic, Goran ^{[11
]}

Svejstrup, Jesper Q. ^{[2
,3
]}

Luijsterburg, Martijn S. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands

[2] Francis Crick Inst, Mech Transcript Lab, 1 Midland Rd, London NW1 1AT, England

[3] Univ Copenhagen, Dept Cellular & Mol Med, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark

[4] Inst Basic Sci, Ctr Genom Integr, Ulsan, South Korea

[5] Ulsan Natl Inst Sci & Technol, Dept Biol Sci, Ulsan, South Korea

[6] Francis Crick Inst, Bioinformat & Biostat, 1 Midland Rd, London NW1 1AT, England

[7] Univ Amsterdam, Canc Ctr Amsterdam, Dept Clin Genet, Sect Oncogenet,Med Ctr, Amsterdam, Netherlands

[8] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI USA

[9] Univ Michigan, Rogel Canc Ctr, Dept Environm Hlth Sci, Ann Arbor, MI USA

[10] Univ Michigan, Ctr RNA Biomed, Ann Arbor, MI USA

[11] Max Planck Inst Multidisciplinary Sci, Dept Mol Biol, D-37077 Gottingen, Germany

来源：

CELL | 2024年 / 187卷 / 25期

基金：

英国医学研究理事会; 欧洲研究理事会; 英国惠康基金;

关键词：

NUCLEOTIDE EXCISION-REPAIR; POLYMERASE-II; COCKAYNE-SYNDROME; UV-IRRADIATION; DAMAGE; VISUALIZATION; RECOGNITION; INITIATION; PROTEIN; CELLS;

D O I：

10.1016/j.cell.2024.10.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryoelectron microscopy (cryo-EM) and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.

引用

页码：7107 / 7125.e25

页数：45

共 88 条

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